Natural Solutions for Inflammation

As a primary defense system of the body, inflammation is critical in both healing and repair following exposure to a wide array of diverse stimuli. These stimuli can include UV radiation from excessive sun exposure, dietary factors like foods with a high glycemic index foods or high in saturated fats, various allergens like pollen, animal dander, certain foods or cosmetics, harmful chemicals, tobacco, alcohol, stress, microbial infections, cuts, burns and many more (See Figure 9).Short term inflammation is self-limiting and stops as quickly as it starts once healing and repair is under control. However, serious problems arise when inflammation continues and becomes a long-term condition. This can occur due to continuous provocation or exposure to inflammation-inducing stimuli (like those shown in Figure 9), the failure of this usually carefully controlled process to stop when it should, or a combination of these two factors. This results in chronic inflammation, which is associated with a whole range of diseases from Alzheimer’s disease to Systemic Lupus Erythematosus and even obesity (see Figure 10).It is unclear at this stage whether inflammation is the cause or the consequence. Much debate rages, nevertheless, the association is very strong, leading some researchers to state that “All roads to chronic diseases lead through inflammation”. The inflammatory process is highly complex and proceeds in a manner that can be described as a domino-like process. The inflammatory response consists of a series of events that involve many players including various cells (mainly white blood cells), and chemicals called cytokines, chemokines, adhesion molecules, growth factors, hormones and the nervous system. The interplay between these players is not completely understood, but the end result is the classical signs of inflammation, namely heat, redness, swelling and pain, plus the (usually temporary) loss of function of the tissue in question.

Molecular Targets for Anti-inflammatory Action

Currently the intricate and complex process of inflammation is far from being completely understood, which means that the control of inflammation presents a huge challenge to scientists and physicians. Nevertheless, research has revealed that there are a number of cracks in the inflammatory armour that can be targeted for therapeutic purposes. Generally these include certain molecules that play key roles in the progression of inflammation. For example, some well-known inflammatory targets include: protein kinases (PK), NF-κB, tumour necrosis factor (TNF), free radicals or radical oxygen species (ROS), and cyclooxygenase (COX enzymes). The way in which each of these can be targeted to control inflammation is discussed below. It must be remembered, however, that these represent only a few players in the inflammatory cycle; there are many more possible targets and the whole process is a biochemist’s nightmare with intricate and often seemingly conflicting interactions and roles between a huge number of molecular factors and chemical signals.

Protein Kinases (PK)

Protein Kinases are a very large family of enzymes including several hundred different but related enzymes. Enzymes in general act to speed up or modify the function of their target, and PK enzymes are no different. Typically PKs achieve their action through a process called phosphorylation, which means that they add a molecule called a phosphate group to their target. The process of phosphorylation changes the structure and thus the function of the enzyme’s target. For example, it is PKs that are responsible for de-activating a particular subunit of a key mediator of inflammation called NF-κB. With this subunit (called IKK) disabled, NF-κB is free to initiate inflammation by reading and activating key inflammatory genes. This process is discussed in more detail b e l ow.PKs are fairly high up in the inflammatory cascade and as one of the early players in the process their job is to fine tune the carefully controlled inflammatory process. Unfortunately, despite the potential for fine control over inflammation, PKs are a huge family of enzymes, responsible for hundreds of different activities in the body. It is incredibly difficult to modulate the function of one specific PK, which means that they are not the ideal target for intervention to treat and control inflammation. Additionally, because there are so many different PKs, and at the moment researchers haven’t figured out which PK acts where. Nevertheless, many natural products do have some influence on various PKs, which does contribute to their anti-inflammatory actions.

NF-κB

NF-κB is complex four protein molecule that acts as a nuclear transcription factor, meaning that it plays a role in controlling whether certain genes are activated or inhibited. The major role of NF-κB is to read (or transcribe) the DNA code and turn on or regulate over 400 genes (out of the 30,000 that we humans have) that will produce specific protein products that play a major role in inflammation and cancer-associated pathologies like invasion, angiogenesis, proliferation and others.

NF-κB was discovered in 1986 and is one of the most researched proteins of the inflammation process. Present in every cell from the fruit fly to man, NF- κB consists of three subunits, two of which activate genes and a third, called IKK, which is an inhibitor that keeps the other two in check. Essentially, once stimulated by any of a multitude of provocative stimuli (see Figure 9) enzymes called protein kinases (PKs) inactivate the inhibitor protein IKK, which frees the two active subunits. The active subunits then move from the cell towards the nucleus where they act to read hundreds of different genes associated with inflammation. Once read, the genes become active, producing a series of downstream products including proteins, receptors, enzymes and other factors like TNF, COX, LOX, IL-2 and others. These products then instigate and sustain the inflammatory process.

Figure 9. Stimuli for Inflammation

NF-κB levels are raised in every inflammatory condition including heart disease, diabetes, allergies, asthma, various forms of arthritis (osteo and rheumatoid), Crohn’s disease, multiple sclerosis, Alzheimer’s disease, osteoporosis and many more (See Figure 10). Unlike PKs, NF-κB is farther down in the process and is thus “closer” to the scene of action. The advantage of targeting NF-κB is three-fold: first, it is a key molecule that can read the inflammatory script allowing expression of various inflammatory genes, second, NF-κB is very well researched and has shown a strong correlation with virtually all inflammatory diseases and third, NF- κB, unlike PKs, is a single molecule, which allows it to be manipulated without significantly affecting other pathways.

TNF-alpha

TNF-α, or Tumour Necrosis Factor alpha, is a molecule that is positioned on the outside of cellular membranes. Once activated by the various provocative stimuli, TNF-α leaves the membrane and “docks” on receptors at distant sites to promote an inflammatory reaction.Regulation of TNF-α is complex and, like many of the inflammatory players, it is a double-agent. At times it can be a beneficial anti-inflammatory agent that helps to destroy tumours and improves healing of damaged tissues, however, at other times acts as an agent provocateur causing damage itself ! In many cases NF-κB will activate TNF-α, however, at other times the reverse can happen, and through a positive feedback loop TNF-α can further activate NF-κB! TNF-α also acts to activate specific downstream inflammatory products like adhesion molecules. These adhesion molecules are akin to the cholesterol plaque that builds up in blood vessels, and they cause damage to the delicate endothelial cells that line the blood vessels and which are vital for the health of the vessels. The ensuing dysfunction of the endothelial cells is one of the major causes of cardiovascular problems.In other cases TNF-α activates proteolytic enzymes like matrix metalloproteins (MMP’s), which is one of the main mechanisms that tumours use to spread to distant sites. Tumours can use enzymes like MMP’s to eat away the surrounding tissue, allowing them to spread into these areas.

Free Radicals – ROS and RNS

There is a constant battle between the forces of good and evil within the body and in every cell. Biochemists refer to these competing forces as antioxidants and oxidants or pro-oxidants (See Figure 11).

Figure 11. Under normal conditions, antioxidants outbalance pro-oxidants, but under oxidative conditions, pro-oxidants prevail over antioxidants, which can lead to many inflammatory diseases, including cancer (from Reuter et al., 2010)

Oxidants are a motley group of reactive oxygen species (ROS) including superoxide anion O2-, hydrogen peroxide H2O2, hydroxyl radical OH- as well as nitrogen species collectively termed reactive nitrogen species (RNS) including 4-hydroxynonenal and various other reactive aldehydes. These molecules or “free radicals” cause much damage to proteins, membranes, DNA and other targets. Certain chemicals or molecules (like cytokines) promote the production of free radicals, and therefore they can be referred to as “pro-oxidants”.Antioxidants are a collection of protective agents that can be produced by the body or derived from the diet. These include glutathione, catalase, superoxide dismutase as well as vitamins C, D and E to name a few. The net effect of all of these antioxidants is to act as scavengers of oxygen and nitrogen free radicals.When oxidative stress occurs as a result of exposure to allergens, radiation or toxic chemicals for example, certain defensive cells like mast cells and white blood cells (leukocytes) are quickly recruited to the site of damage which leads to a “respiratory burst” releasing both ROS and RNS into the area. In the short term ROS and RNS are beneficial and have the effect of neutralizing the offending stimuli and causing acute inflammation. If however, the stressors persist, the continued production of these free radicals begins to cause damage to the healthy tissue. A therapeutic strategy involves neutralizing both ROS and RNS after the initial acute inflammatory process.

COX Enzymes

Cyclooxygenase is a family of enzymes that work on arachidonic acid, which is a component of the cell membrane. There are two major types of COX enzymes, referred to as COX-1 and COX-2. The former is a housekeeping enzyme that works on maintaining homeostasis or status-quo of the cells. It is an essential enzyme without which cells would be unable to maintain a healthy state. COX-2, on the other hand, is an enzyme that is induced by many of the factors responsible for inflammation: stress, UV light, toxins etc. COX-2 generates a series of products called prostaglandins (specifically PGE2) that are highly inflammatory.Several pharmaceutical drugs target COX-2 without affecting COX-1; these are called COX-2 selective drugs. Celebrex® and Vioxx® are examples of this type of anti-inflammatory pharmaceutical. Unfortunately, some of these drugs can cause harmful side-effects like kidney, liver and gastrointestinal damage, and as result they have had to be withdrawn from the market.

Natural Anti-inflammatory Agents

With so many factors at work, how does one put out all of these inflammatory fires within? Although this is a huge challenge, the numerous pathways allow an opportunity to tackle a multitude of mechanisms simultaneously. Unlike pharmaceuticals that only address one specific pathway, like the classic silver bullet mechanism of action of COX-inhibitors, natural products tend to have much more widespread activity. Nature is full of anti-inflammatory agents that target many of the pathways associated with inflammation. In fact, unlike pharmaceuticals that have a single target, natural products often have multiple mechanisms. Because we do not yet know which pathways are most critical, this multi-targeted approach to inflammation makes more sense, at least for now since single-targeted therapy has shown little promise. Moreover, an added advantage is that multi-targeted natural products are generally safer since a lower dose is required than for pharmaceuticals.

Boswellia serrata

The herb Boswellia serrata or Indian frankincense has been used in Ayurveda for thousands of years for a multitude of diseases. The empirical evidence or its anti-inflammatory benefits is strong. More recently, researchers have conducted animal and human studies to verify these anti-inflammatory effects, with several human studies showing very positive results for Boswellia’s anti-inflammatory benefits. An incredibly important aspect of Boswellia is that it does not have a significant immediate effect on inflammation. One study found that while Boswellia showed no significant effect on inflammation in the first month of use, from the second month onward, symptoms were reduced to the same degree as with powerful COX-2 inhibitor pharmaceuticals. All of this was without the side effects associated with COX-2 inhibitors, and, amazingly, the reduction of inflammation in those taking Boswellia was maintained even.

What’s the Deal with Bioavailability?

Poor bioavailability is a problem that has plagued many natural supplements over the years. Simply put, bioavailability is the percentage of an ingested ingredient that makes it into your bloodstream, where it can exert a physiological effect. For example, something like curcumin, the active medicinal antioxidant found in turmeric root, has incredibly poor bioavailability; up to 8 grams of pure curcumin can be consumed without gaining ANY detectable levels in the blood. Because of these bioavailability issues, many ingredients that have shown incredibly promising results in early in vitro studies end up having their benefits significantly reduced or even completely eliminated when the ingredient is taken by humans! This has led scientists to look into the causes of poor bioavailability and also to develop a variety of technologies and strategies that can be used to help enhance the bioavailability of molecules, allowing their benefits to be better harnessed in medications and natural supplements.There are several factors that can cause a substance to be poorly bioavailable:

1. Poor solubility – Many medicinal herb extracts, vitamins and cofactors are what scientists call ‘hydrophobic’, meaning they do not dissolve in water. Much of digestion is based on solubility in water, so many of these end up passing straight through the GI system with little medicinal effect.

2. Low stability – Many molecules have low stability in the digestive system. The process of digestion, combining the low pH of the stomach and the higher pH of the intestines, both full of powerful enzymes, break down many molecules that could be beneficial

.3. Absorption – If a molecule survives the harsh conditions of the digestive tract and is successfully solubilized by the body, it still needs to be absorbed. This is more difficult than one might think, because the body is very selective, especially when it is something outside of the normal regime of carbohydrates, proteins and fats that the GI system is designed to absorb.

4. Metabolism – Poorly bioavailable molecules and extracts are also often degraded by the body, because they are recognized as ‘foreign’, even if they have helpful medicinal properties. This system is highly important, because, while it may frustrate us by causing low bioavailability of supplements that we want to absorb, it also results in the detoxification of molecules that are dangerous.

How can Bioavailability be increased?

There are many ways to get around the bioavailability problem, by improving each of the above limiting factors.

Many approaches aim to increase all of these factors, but the real question is, is this wise? Tests on the ingredients in supplements have shown that most can be safely taken at higher doses, which indicates that increasing bioavailability is safe, but is that the only concern? One very common method to increase bioavailability is the inclusion of piperine, a component of black pepper extract. This molecule inhibits the degradation of all foreign molecules. This works very well to increase bioavailability, but has the unintended effect of increasing the amounts of toxins, carcinogens and chemicals retained by the body.If altering the metabolism of a compound can have negative effects, are there ways to safely increase bioavailability? Definitely. Three of the best ways to increase bioavailability are by improving the solubility, stability and absorption of compounds. Unlike the overly complicated nano-technology used by the pharmaceutical and biotechnology industries, like nano-tubes or other structures, the nano-technology used by the food industry makes use of particle size reduction and various methods to prevent particle clumping. The latter technology is safe and uses ingredients that are safe for use in foods, and it is a strategy that can also be safely and effectively applied to natural health supplements.

It is a common theme that virtually all natural anti-inflammatory ingredients also have an anti-cancer effect

after patients stopped taking it for a month! A large family of compounds called saponins, and in particular the boswellic acids (BA), have been confirmed as the principal active compounds in this plant. Boswellic acids likely have the most powerful anti-inflammatory effect of all natural products! It is a common theme that virtually all natural anti-inflammatory ingredients also have an anti-cancer effect. Recall earlier in this issue of Advances we discussed that the German pathologist Virchow made a unique observation that the site of inflammation was often accompanied by cancers at the same site. Boswellia has been shown to exert anti-cancer effects in-vitro and in animal studies, where it has been shown to reduce both tumour burden and frequency. In terms of its effects on inflammation in humans, a recent German clinical study showed that inflammation of the brain could be significantly reduced by bioavailable Boswellia extracts which prevented edema, one of the hallmark signs of inflammation. Furthermore, Boswellia has been shown in clinical trials to be more effective than conventional NSAID’s, like ibuprofen, for the treatment of symptoms associated with osteoarthritis. Moreover, Boswellia extract showed fewer gastrointestinal and kidney side effects than ibuprofen.Boswellia’s anti-inflammatory action has also resulted in several human trials looking at its potential use in the treatment of inflammatory conditions of the bowel including ulcerative colitis and Crohn’s disease. So far, the results of have been mixed, with some reporting good results and others reporting no effect. One possible reason for this discrepancy is that Boswellia, like many natural products, has a huge bioavailability issue (see Note: What’s the Deal with Bioavailability?). It is conceivable that studies that did not report any effect could have used products that were poorly bioavailable. Food science nano-technology is a safe and effective way of improving the Advances 27bioavailability of many products like Boswellia.Finally, Boswellia has been shown to exert a powerful protective effect on the stomach. Boswellia extracts have been shown to prevent or reduce gastric ulcers, yet another action that can be linked to its anti-inflammatory effects.

Curcumin

Curcumin is one of the three active components called curcuminoids that are present in turmeric root, a spice widely used by many cultures for culinary, colouring and healing purposes. Curcumin accounts for approximately two thirds of all curcuminoids in the root, with the other two (demethoxycurcumin and bisdemethoxycurcumin) making up the remaining third. In Ayurveda and the traditional Chinese system of medicine, curcumin has been used for a wide range of conditions including, fever, liver and gall bladder ailments, diabetes, heart conditions, gastric problems, skin conditions, infections, diarrhea, memory, cancers and many more.Curcumin is possibly the most widely researched natural product available, with thousands of in vitro mechanistic and animal studies to back up its effects. More recently, further support for the benefits of this spice has come from a large number of studies in humans, with several dozen human studies being conducted using curcumin every year! The results of this immense body of research have repeatedly confirmed that curcumin possesses not only powerful anti- inflammatory properties, but also antioxidant, anticancer and neuroprotective effects.

The key anti-inflammatory actions of curcumin

• Potently reduces NF-κB by both preventing the activation of PKs so the inhibitor IKK remains active and keeps NF-κB in check and by directly breaking down excess NF-κB.

• Inhibits other inflammatory mediators like TNF-α, the various interleukins and others

• In the central nervous system, curcumin stimulates phagocytes so that Aβ is rapidly cleared. This effect is enhanced in the presence of vitamin D.

• Stimulates the proliferation of nerve cells.

• Reduces the COX-2 enzyme selectively without significantly affecting the housekeeping enzyme COX-1, all without the gastric, kidney and cardiovascular side effects of pharmaceutical NSAID’s and COX-2 inhibitors.

• Chelates heavy metals like copper and iron which are known to cause inflammation via enzymatic reactions that produce free radicals.

• Directly quenches both oxygen and nitrogen free radicals, which are primary sources of inflammation.

• Limits arachidonic acid release from cellular membranes by inhibiting an enzyme called phospholipase A2. As a result, there is less substrate for COX and LOX enzymes to work on, reducing the production of inflammatory molecules.

Recent research suggests that green tea polyphenols act through over two dozen different mechanisms

As an anti-inflammatory molecule, curcumin significantly reduces a huge number of inflammatory biomarkers, especially the very important NF-κB.Bharat Aggarwal at Texas A&M University is a world leader in curcumin and inflammation research. Aggarwal has published hundreds of reviews and original research on this fascinating molecule. Aggarwal is a strong proponent of reduction of NF-κB as a means of reducing the effects of chronic inflammation. Overall, his research has concluded that curcumin’s anti-inflammatory properties are wide ranging, and include a variety of different mechanisms and targets. It must be pointed out that curcumin has a huge bioavailability issue. Bioavailability refers to the amount of the active compound that reaches the target site. In the case of curcumin, for example, this would be the amount that reaches the nerve cells in the brain or the joints, liver, kidneys or other target tissues. There are many possible reasons for the poor bioavailability of curcumin. For example, the curcumin molecule isn’t very soluble in the digestive tract, As an anti-inflammatory molecule, curcumin significantly reduces a huge number of inflammatory biomarkers, especially the very important NF-κB.Bharat Aggarwal at Texas A&M University is a world leader in curcumin and inflammation research. Aggarwal has published hundreds of reviews and original research on this fascinating molecule. Aggarwal is a strong proponent of reduction of NF-κB as a means of reducing the effects of chronic inflammation. Overall, his research has concluded that curcumin’s anti-inflammatory properties are wide ranging, and include a variety of different mechanisms and targets. It must be pointed out that curcumin has a huge bioavailability issue. Bioavailability refers to the amount of the active compound that reaches the target site. In the case of curcumin, for example, this would be the amount that reaches the nerve cells in the brain or the joints, liver, kidneys or other target tissues. There are many possible reasons for the poor bioavailability of curcumin. For example, the curcumin molecule isn’t very soluble in the digestive tract, it is unstable due to pH conditions, it is too big to be easily absorbed by the gastrointestinal tract and finally, it is rapidly broken down by the detoxification enzymes that protect the body. Numerous approaches have been utilized to improve the bioavailability of curcumin, for example, using smaller particles of curcumin can have a significant effect on improving the bioavailability of this beneficial molecule. For more information about improving bioavailability, see the Note in this article: “What’s the Deal with Bioavailability?”

Green Tea Polyphenols

Green tea is another widely studied natural product. The active components in green tea are a group of polyphenols called catechins, including epigallocatechin gallate (EGCG). These catechins are typically found in unfermented green tea leaves. Fermented black tea leaves generally have little or no catechin content, but instead are high in theaflavins, which have different physiological actions.Catechins and other polyphenols have been shown to act at multiple sites in the inflammatory cascade. For example, they act to quench oxygen and nitrogen free radicals, inhibit COX-2 enzymes, and prevent the IKK from being inactivated, thus preventing NF-κB from becoming activated. Green tea also prevents TNF and other signaling molecules from being activated. More recent research suggests that green tea polyphenols act through over two dozen different mechanisms, much like the curcumin molecule. Clinical research also suggests that EGCG has a powerful anti-cancer effect, especially for breast, prostate, skin and colon cancers. These anti-cancer effects could be closely linked to EGCG’s role in inhibiting inflammation.

Omega 3 fatty acids rich in EPA and DHA

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are two of the many omega-3 fatty acids found in nature, and especially in fatty fish like salmon and anchovies. Plant sources of omega-3 fatty acids are also becoming more common. For example, algae are an excellent source of DHA, and nowadays algae can be commercially harvested under controlled conditions. Most other plant sources contain predominately other omega-3 fatty acids, like alpha linolenic acid, which are not converted very efficiently into EPA/DHA. New research is starting to look at the potential to extract EPA from algae sources as well. Many of us have heard that omega-3 fatty acids are important for good health, and part of this health benefit comes from the role they play in reducing inflammation. Arachidonic acid (AA) is abundantly present in the membranes of cells. When a cell is exposed to an inflammatory stimulus, an enzyme called phospholipase is released that causes AA to leave the membrane and move into the interior of the cell. Inside the cell, two sets of enzymes called COX and LOX utilize AA breaking it down to two highly inflammatory molecules called prostaglandin E2 (PGE2) and leukotriene B4 (LTB4). EPA and DHA are important because they can actually take the place of AA in cell membranes. In individuals with a high intake of EPA/DHA the cell membranes contain more EPA and DHA and less AA. As a result, when provoked by inflammatory signals, EPA or DHA leaves the cell membrane instead of AA. COX and LOX enzymes then act on these fatty acids, but instead of forming the highly inflammatory PGE2 or LTB4 that come from AA, they form fairly innocuous and non-inflammatory molecules.Additionally, both EPA and DHA have been shown to possess potent anti-inflammatory properties in their own right. For example, in animals fed DHA and then provoked with an inflammatory stimulus, the amount of resulting inflammation is considerably reduced. Similarly, in humans a high intake of EPA and/or DHA significantly reduces key inflammatory markers like TNF and NF-κB. Furthermore, omega-3 fatty acid intake has been shown to reduce the intake of NSAIDs by arthritis patients. DHA intake is also associated with a reduced risk of Alzheimer’s disease. For example, research has shown that restricting DHA in laboratory animals increases their risk of Alzheimer’s disease while the addition of DHA to the diet reduces the pathology of the disease. Similarly, EPA has been shown to powerfully reduce inflammation of the blood vessels. Not only do omega-3 fatty acids act as anti-inflammatory molecules, they also act directly as antioxidants by quenching free radicals of oxygen and nitrogen species and indirectly by boosting the body’s own antioxidant defense system through the stimulation of antioxidant enzymes like catalase, superoxide dismutase and glutathione peroxidase.

Ashwagandha

Ashwagandha is another Ayurvedic herb that has been used for centuries. Often but erroneously called the Indian ginseng, ashwagandha is a powerful anti-inflammatory agent with a strong action against NF-κB. Ashwagandha has been shown to accelerate the breakdown of NF-κB, which is different than other natural agents that act to prevent its activation in the first place. As such, ashwagandha provides a unique alternative pathway for reducing NF-κB levels, and thus inflammation. Unfortunately, while ashwagandha has excellent supporting empirical data, there are few well controlled human studies that have examined its anti-inflammatory action. Nevertheless, animal studies confirm that ashwagandha, and its active components the sitoindosides, are powerful anti-inflammatory agents. In addition to this, ashwagandha has been shown to have other physiological effects, including anti-cancer actions, anxiety reducing properties and a powerful immune system stimulating effect. It can therefore be speculated that since ashwagandha acts to stimulate the immune system (particularly the action of macrophages), its use in conjunction with more traditional and well known anti-inflammatory herbs like curcumin and Boswellia could result in the exertion of a more powerful anti-inflammatory effect.

Putting it all Together

In the end, there are a wide variety of powerful natural herbs and molecules that have shown very promising results for the reduction and prevention of inflammation. The advantage of these natural anti-inflammatory agents is that they act through a variety of mechanisms and influence a wide range of targets and molecules involved in the body’s inflammatory response. These natural agents are safe and effective, and can be used in combination to help control and prevent chronic inflammation throughout the body. By preventing and treating chronic inflammation, it may be possible to reduce the risk and progression of many serious diseases that have been linked to inflammation. Finally, through the use of various novel techniques to improve bioavailability, the full extent of the benefits of these natural anti-inflammatory agents can be realized.

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